ABSTRACT This revised application proposes to conduct a randomized, double blind, placebo-controlled combined laboratory and clinical outcome study to test the efficacy of Prazosin (PZ) in decreasing alcohol craving, anxiety, stress dysregulation and alcohol use outcomes in treatment seeking alcohol dependent (AD) individuals with and without current anxiety disorders (+Anx/-Anx). In previous research we've shown that laboratory exposure to stress and alcohol cues increases alcohol craving, anxiety and stress dysregulation, which in turn, are predictive of subsequent alcohol relapse outcomes. Prazosin, an alpha-1 adrenergic antagonist, known to decrease central norepinephrine and CRF upregulation, decreases stress-induced alcohol reinstatement and alcohol consumption in both dependent rats and in a preliminary study with alcoholic patients. However, the specific mechanisms by which PZ may be decreasing alcohol consumption in humans is not understood. Our preliminary data show that PZ relative to Placebo (PL) decreases stress and cue- induced alcohol craving, anxiety and stress dysregulation in AD individuals, and that such decreases are more pronounced in AD individuals with current anxiety disorders than those without such comorbidity. Thus, in light of previous research and our preliminary findings, we propose a 5-year study that will recruit 150 AD individuals (evenly split by those with and without any current anxiety disorders) to participate in a randomized, double blind, placebo-controlled 12-week clinical laboratory and outcome study. The following specific aims will be addressed: 1) To evaluate the effects of PZ (16 mg, tid) on stress and cue-induced alcohol craving and anxiety, stress dysregulation in the laboratory in AD patients with and without current anxiety disorders; (2)To evaluate the effects of 16mg PZ on alcohol craving, anxiety and stress dysregulation in AD patients with current anxiety disorders as compared to those without anxiety disorders; (3) To determine the efficacy of 12- week PZ treatment on primary alcohol use outcomes, and secondary outcomes including alcohol craving, negative mood symptoms, smoking and sleep; (4) To assess the efficacy of 12-week PZ versus PL treatment on primary alcohol use and secondary outcomes in alcoholics with/without any current anxiety disorders. (5) To examine one-month post-treatment follow-up alcohol use outcomes for enduring short term treatment effects. The role of patient characteristics and laboratory-based craving and stress dysregulation in predicting alcohol treatment outcome will also be explored. If the proposed hypotheses are supported, it will provide evidence for efficacy of Prazosin as a medication for alcoholism, particularly for those with co-morbid anxiety disorders.